Leukocyte chemotaxis plays a critical in the body's defense against microorganisms and hyperactivity of these cells leads to a variety of pathologic states including inflammation, vasculitis, and glomerulonephritis. Chemotaxis is dependent on the dynamic activity of adhesive and actin cytoskeletal structures that regulate cell motility. Rho GTPases are central players in the regulation of cell adhesion and actin cytoskeletal polymerization and assembly into cytoskeletal structures. We have found that Vav family Rho GTPase exchange factors are required for chemotaxis mediated by the chemoattractant fMLP and for macrophage migration on an extracellular matrix. This conclusion was based on studies of mice deficient in two Vav family members, Vav1 and Vav3. This proposal will examine the mechanisms involved in activation of Vav by chemoattractants and integrins and establish the mechanisms whereby this multidomain scaffolding protein regulates actin cytoskeletal structures and controls cell migration. The latter will involve defining regions of Vav that are required for motility and identification of effectors that mediate the activity of these domains. In addition we will analyze neutrophil and macrophage motility in mice lacking all three Vav family members since they are all expressed in these two cell types. These studies promise to elucidate pathways that are important in the host defense again microorganisms and pathologic inflammatory states.